Evidence points to a positive influence of estrogen for memory processes that depend on the hippocampus, including postponement of age-related memory impairments. However, estrogen effects are diverse and the challenge remains to determine which biological mechanisms are important for estradiol (E2) effects on cognition. The discovery of several different nuclear estrogen receptors (ERs) and emerging evidence for rapid nongenomic influences on second messenger signaling cascades makes this challenge more formidable. Our long-term goal is to understand mechanisms of estrogen action on the hippocampus, which influence memory over the life span. E2 rapidly influences physiological processes in a manner opposite that observed during aging. However, E2 responsiveness decreases with advanced age possibly due to a loss of ERalpha associated transcription. The current study will determine which hippocampal genes are linked to ERalpha activity. It is hypothesized that ERalpha-linked genes regulate the responsiveness of rapid E2 effects and a decrease in activity is associated with functional brain aging and memory decline. Specific aim 1 will test the hypotheses that E2 influences transcription of functionally associated genes involved in brain aging using microarray technology. Specific aim 2 will employ ER knockout mice to test the hypothesis that ERalpha is important in the regulation of genes associated with aging and memory function. Specific aim 3 will test the hypothesis that ERalpha contributes to E2 responsiveness for second messenger signaling pathways using electrophysiology and second messenger assays to compare responses in wildtype and knockout mice. Specific aim 4 will use viral vector-based gene delivery to restore ERalpha function in the hippocampus in vivo. ERalpha may be a good test case for examining the function of a specific gene in memory since ERalpha knockout mice exhibit a gene dose impairment in memory function such that delivery would be expected to have a dramatic consequences on memory.